Mast cells are selecfively found in relatively large numbers immediately beneath the epithelial surfaces of the skin and mucosae of the genitourinary, gastrointestinal, and respiratory tracts and represent one of the first cells of the innate immune system encountered by an invading pathogen. An important result of the interaction of MCs with invading microorganisms or their products is the secretion of various preformed and nduced mediators. The most frequently detected product elicited by this interaction is histamine, a potent vasoacfive mediator of acute inflammafion, and regulator of antigen-specific adaptive immune responses. The immunoregulatory effect of histamine on cells of the innate and adapfive immune system is mediated by differenfial expression of four types of histamine receptors: HI, H2, H3 and H4. In the mouse model of coxsackievirus B3 (CVB3)-induced myocardifis, degranulafing MC are observed in the heart, pancreas, liver and spleen within 6 hours of infecfion; moreover, myocardifis suscepfible mice have significantly greater numbers of both granulated and degranulating MC. Importantiy, CVB3-induced MC degranulafion leads to increased histamine levels. We have found that naVve T-cells express HIR, H2R and H4R but do not express the H3R and that upon acfivafion rapidly downregulate the expression of all three receptor types; however, CD4 memory T-cells selecfively express the H3R. Furthermore, mice deficient in H2R and H4R develop significanfiy less myocardifis than wild-type (WT) mice. Changes in disease suscepfibility correlate with alterations in cytokine expression by CD4 T-cells from infected mice with H4RK0 mice showing an enhanced CD4 Th2 bias. Clearly, histamine and its receptors have the potenfial to play a major role in regulafing anfigen-specific adapfive immune responses following CVB3 infection. The studies proposed in this project provide a crifical link between a mediator released by one of the first cells of the innate immune system to interact with pathogenic microorganisms and the anfigen-specific adapfive immune responses which they elicit. In this applicafion we will test the hypotheses that following CVB3 infecfion (1) H2R and H4R signaling in CD4 T-cells regulates effector T-cell funcfions which in turn determine suscepfibility and (2) H3R signaling regulates CD4 memory T-cell responses.